Understanding the role and regulation of TTBK1/2 during neurodegenerative disease progression

Thesis (Ph.D.)--University of Washington, 2018A number of neurodegenerative diseases are characterized by the deposition of abnormally phosphorylated tau or TDP-43 in disease-affected neurons. Recent studies have suggested that phosphorylated species of tau and TDP-43 may be the driver behind neurodegeneration in these diseases. A screen for novel TDP-43 kinases identified the Tau Tubulin Kinases 1 and 2 (TTBK1/2), a pair of kinases that were originally characterized by their ability to phosphorylate tau. The function and regulation of TTBK1/2 in adult brain is unknown and there is no current understanding of what role they may play in disease progression. Preliminary studies show increased expression of TTBK1/2 in FTLD-TDP and ALS brain tissue, indicating that the TTBKs may be misregulated during disease. In this body of work, I followed up on these initial findings. I show that co-expression of TDP-43 and TTBK1 and co-expression of tau with both TTBK1 and TTBK2 in C. elegans causes exacerbation of behavioral abnormalities, increased pathological protein phosphorylation, and aberrant neuronal architecture and loss. I also show that TTBK1 is upregulated and processed in a number of tauopathies including FTLD, PSP, CBD, and Pick’s disease. Lastly, I identified an array of proteins that interact with the various domains of both TTBK1 and TTBK2 and may be potential regulators of kinase activity or provide insight into the role that TTBK1/2 play in the brain. These findings have expanded our understanding of the way that TTBK1/2 function and has the potential to lead to the development of targeted therapies for both tau and TDP-43 proteinopathies